NM_000465.4(BARD1):c.2268G>A (p.Trp756Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Sep 20, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000164774.5

Allele description [Variation Report for NM_000465.4(BARD1):c.2268G>A (p.Trp756Ter)]

NM_000465.4(BARD1):c.2268G>A (p.Trp756Ter)

Gene:

BARD1:BRCA1 associated RING domain 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

2q35

Genomic location:

Preferred name:

NM_000465.4(BARD1):c.2268G>A (p.Trp756Ter)

HGVS:

NC_000002.12:g.214728742C>T
NG_012047.3:g.85970G>A
NM_000465.4:c.2268G>AMANE SELECT
NM_001282543.2:c.2211G>A
NM_001282545.2:c.915G>A
NM_001282548.2:c.858G>A
NM_001282549.2:c.729G>A
NP_000456.2:p.Trp756Ter
NP_001269472.1:p.Trp737Ter
NP_001269474.1:p.Trp305Ter
NP_001269477.1:p.Trp286Ter
NP_001269478.1:p.Trp243Ter
LRG_297t1:c.2268G>A
LRG_297:g.85970G>A
LRG_297p1:p.Trp756Ter
NC_000002.11:g.215593466C>T
NG_012047.2:g.85963G>A
NM_000465.2:c.2268G>A
NR_104212.2:n.2233G>A
NR_104215.2:n.2176G>A
NR_104216.2:n.1432G>A
p.W756*

Protein change:

W243*

Links:

dbSNP: rs786202118

NCBI 1000 Genomes Browser:

rs786202118

Molecular consequence:

NR_104212.2:n.2233G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104215.2:n.2176G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_104216.2:n.1432G>A - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NM_000465.4:c.2268G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001282543.2:c.2211G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001282545.2:c.915G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001282548.2:c.858G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001282549.2:c.729G>A - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000215450	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Sep 20, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000215450

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Sep 20, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Ambry Genetics, SCV000215450.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The p.W756* variant (also known as c.2268G>A), located in coding exon 11 of the BARD1 gene, results from a G to A substitution at nucleotide position 2268. This changes the amino acid from a tryptophan to a stop codon within coding exon 11. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BARD1, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 22 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on internal structural analysis, this alteration is expected to remove a significant portion of a phosphopeptide binding site (Birrane G et al. Biochemistry. 2007 Jul; 46(26):7706-12; Rodriguez M et al. J. Biol. Chem. 2003 Dec; 278(52):52914-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 8, 2024

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